Acetidine derivatives

ABSTRACT

A new azetidine derivative of the formula: ##EQU1## wherein R 1  represents a penicillin- or cephalosporin-amido group, R 2  represents one of the groups of the following formulae: ##EQU2## wherein R 4 , R 5  and R 6  are the same or different and each represents a hydrogen atom or a lower alkyl or alkenyl group, n represents 2 or 3 and - in case formula IIB represents a phenyl group - this group may carry one to four further substituents selected from the group consisting of halogen atoms and lower alkyl, lower alkenyl and phenyl groups, 
     R 3  represents an amino group of the formula ##EQU3## wherein R 7  represents a hydrogen atom or a lower alkyl group and R 8  represents a lower alkyl group, or 
     R 3  represents a N,N&#39;-disubstituted hydrazino group wherein the substituents are lower alkyl groups, e.g. the N,N&#39;-diisopropylhydrazino group, or 
     R 3  represents the group --OR 9 , wherein R 9  represents a hydrogen atom, a lower alkyl group, which group may be substituted by 1 to 3 halogen atoms or by 1 or 2 phenyl groups, werein the phenyl groups may be substituted by a methoxy or a nitro group, or R 9  represents a phenacyl group or a salt-forming cation, 
     And corresponding azetidine derivatives of formula I wherein the double bond in the propenyl side chain has been shifted from the 2- to the 1-position, which are versatile intermediates in the process of preparing cephalosporanic and penicillanic derivative.

This is a division of Ser. No. 440,725, filed Feb. 8, 1974.

This invention relates to new azetidine derivatives, to a process fortheir preparation, and to a new process for the preparation ofcephalosporanic acid derivatives using the azetidine derivatives asstarting materials.

It is an object of the present invention to provide hitherto unknownazetidine derivatives conforming to the general formula: ##EQU4##wherein R₁ represents a penicillin- or cephalosporin-amido group, R₂represents one of the groups of the following formulae: ##EQU5## whereinR₄, R₅ and R₆ are the same or different and each represents a hydrogenatom or a lower alkyl or alkenyl group, n represents 2 or 3 and - incase formula IIB represents a phenyl group - this group may carry one tofour further substituents selected from the group consisting of halogenatoms and lower alkyl, lower alkenyl and phenyl groups,

R₃ represents an amino group of the formula ##EQU6## wherein R₇represents a hydrogen atom or a lower alkyl group and R₈ represents alower alkyl group, or

R₃ represents a N,N'-disubstituted hydrazino group wherein thesubstituents are lower alkyl groups, e.g. the N,N'-diisopropylhydrazinogroup, or

R₃ represents the group --OR₉, wherein R₉ represents a hydrogen atom, alower alkyl group, which group may be substituted by 1 to 3 halogenatoms or by 1 or 2 phenyl groups, wherein the phenyl groups may besubstituted by a methoxy or a nitro group, or R₉ represents a phenacylgroup or a salt-forming cation,

and corresponding azetidine derivatives of formula I wherein the doublebond in the propenyl side chain has been shifted from the 2- to the1-position.

For the purposes of this application the latter azetidine derivativeswill be indicated by the term "iso-azetidine derivatives".

By the expression "penicillin- or cephalosporin-amido group" is meant a6β-acylamido group, which is known to those skilled in the art, in bothnatural and synthetic penicillins and cephalosporins.

By the terms "lower alkyl" and "lower alkenyl" as employed herein, aloneor in conjunction with other designated groups, is meant straight- orbranched-chain alkyl and alkenyl groups containing from one to fourcarbon atoms, e.g. methyl, ethyl, allyl, isopropyl, butyl, and t-butyl.Similarly, the term "lower alkoxy" as used herein, alone or inconjunction with other designated groups, means straight-chain orbranched-chain alkoxy groups containing from one to four carbon atoms.The halogens referred to may be chlorine, bromine, iodine or fluorine.

By the term "salt-forming cation" as used for symbol R₉ is meant alkalimetal and alkaline earth metal ions, for example sodium, potassium andcalcium ions.

Preferably, the symbols R₄, R₅ and R₆ in the formulae IIA to IIDrepresent a hydrogen atom or a methyl or ethyl group. Suitable groupsrepresented by the formula: ##EQU7## are, for example: succinimido,phthalimido, hexahydrophthalimido, 1,5,5-trimethylhydantoin-3-yl,3,3-dimethylglutarimido, 3-ethyl-3-methylglutarimido and5-ethyl-1-methyl-5-phenyl-2,4,6-trioxohexahydropyrimidin-3-yl. R₃preferably represents the group --OR₉, wherein R₉ represents a hydrogenatom, a methyl or benzyl group or a sodium or potassium ion.

According to a feature of the present invention the azetidinederivatives of general formula I are prepared by the process whichcomprises reacting a penicillanic sulphoxide derivative of the generalformulae: ##EQU8## wherein R₁ is as hereinbefore defined, and R₃ ' hasthe same significance as defined above for symbol R₃, except that whenR₃ ' represents a group --OR₉, R₉ does not represent a salt-formingcation, but R₉ moreover represents a silyl group of one of the followingformulae: ##EQU9## wherein the symbols R₁₀ are the same or different andeach represents a lower alkyl or alkoxy group (optionally substituted byhalogen atoms), or a phenyl group, X represents a halogen (preferablychlorine) atom and R₁₁ represents a penicillanic sulphoxide acyl groupof the general formulae: ##EQU10## wherein R₁ is as hereinbeforedefined, with a silicon-containing compound of the general formula:##EQU11## wherein R₂ and R₁₀ are as hereinbefore defined, underanhydrous conditions, in an inert organic solvent at temperaturesbetween 50° and 180°C.

As is apparent from the formulae III the oxygen atom of the sulphoxidegrouping may be in β- or α-position in relation to the penicillinnucleus; in this application these isomers are referred to as S- andR-sulphoxides, respectively.

Preferably, the symbol R₃ ' in the starting materials of formulae IIIAand B a group --OR₉, wherein R₉ represents a hydrogen atom, a methyl orbenzyl group, or a silyl group as defined herein above. Suitable silylgroups are for example: triethoxysilyl, tributoxysilyl, dimethoxymethylsilyl, diethoxy methylsilyl, dimethyl methoxysilyl, dimethylethoxysilyl, butoxy dimethylsilyl, tri(2-chloroethoxy)silyl,tri(2-chloropropoxy)silyl, trimethyl silyl, diphenyl methylsilyl, etc.

The reaction is advantageously carried out at a temperature between 70°and 120°C, depending on the reflux temperature of the solvent employed.Reaction times of 15 minutes to one day appeared to be necessary forgood conversion yields (e.g. of up to 70% of the theoretical yield) inthe indicated temperature range.

Examples of silicon-containing compounds of formula V which may beutilized in the aforesaid process are succinimides, phthalimides,hexahydrophthalimides, hydantoins, glutarimides and barbiturates,substituted on the nitrogen atom by the group(R₁₀)₃ Si-- wherein R₁₀ isas hereinbefore defined and is preferably a methyl group. Specificexamples of such reactants are N-trimethylsilylsuccinimide,3-trimethylsilyl-1,5,5-trimethylhydantoin, N-trimethylsilylphthalimide,N-trimethylsilylhexahydrophthalimide,N-trimethylsilyl-3,3-dimethylglutarimide,N-trimethylsilyl-3-ethyl-3-methylglutarimide and3-trimethylsilyl-5-ethyl-1-methyl-5-phenyl-2,4,6-trioxohexahydropyrimidine(3-trimethylsilyl-5-ethyl-1-methyl-5-phenyl-malonylurea).

The molar amount of the silicon-containing compound according to formulaV which has to be employed depends on the significance of symbol R₃ ' informulae IIIA or B. When the said symbol represents a hydroxy group,sufficient silicon-containing compound must be used as to silylate thecarboxy group of the penicillanic sulphoxide before thesulphur-containing ring is opened. When R₃ ' represents a hydroxy group,at least 3 moles of the silicon reactant of formula V are employed permole of penicillanic sulphoxide. Advantageously still larger molaramounts of the silicon reactant (up to 50 moles per mole of sulphoxide)are used. The silicon-containing compound may then even act as thesolvent wherein the reaction is carried out.

Usually however, an additional solvent is added to the reaction mixture.The inert organic solvents employed in the process are those whichcannot influence the reaction, i.e. preferably consisting of moleculeswhich are not silylated under the reaction conditions employed.Advantageously aprotic polar solvents are used.

Examples of suitable solvents are: hexamethylphosphotriamide,dimethoxyethane, N,N-diethylmethylsulphonamide and methylisobutylketone. Preferred solvents are: benzene, toluene, acetonitrile,benzonitrile, nitrobenzene, N,N,N',N' -tetramethylurea,N-acetylsuccinimide, N-acetylphthalimide,3-acetyl-1,5,5-trimethylhydantoin, dimethylacetamide anddimethylformamide. Particularly, preferred are the latter six solventsor mixtures of these. Sometimes the yield of the process can be improvedby adding acetic acid or trimethylsilyl acetate to the reaction mixture.

When starting materials of formulae III A or B are used in the free acidform, i.e. when R₃ ' represents a hydroxy group, the penicillanicsulphoxide acid will first be silylated by reaction with thesilicon-containing compounds of formula V, whereupon these silylatedpenicillanic sulphoxide derivatives will be converted with furtheramounts of the silicon-containing compounds of formula V into azetidinederivatives of general formula I, wherein the acid group is silylatedtoo.

During the further isolation and/or purification processes the silylgroup is removed again form the azetidine compound, thus resulting in anazetidine derivative of general formula I in the free acid form or asalt thereof, i.e. wherein R₃ represents a hydroxy group or R₃ is agroup --OR₉, wherein R₉ represents a salt-forming cation as definedhereinbefore.

Whether the azetidine derivative of formula I is obtained in the form ofa free acid or a salt thereof depends on the isolation and purificationprocedures employed.

It will be appreciated that when starting materials of formulae III A orB, wherein R₃ ' is a group --OR₉ and R₉ represents a silyl group offormulae IV A to C, are used, the process will proceed in the same wayand will also result in azetidine derivatives of formula I in the freeacid form or a salt thereof, obtained via corresponding intermediatesilylated azetidine derivatives. On the other hand, when R₃ ' in thestarting penicillanic sulphoxide derivatives of formulae III A or Brepresents an amino group ##EQU12## wherein R₇ and R₈ are ashereinbefore defined, or represents a N,N'-disubstituted hydrazino groupas defined hereinabove, or a group --OR₉, wherein R₉ is as hereinbeforedefined in relation to formula III, but does not represent a hydrogenatom or a silyl group of formulae IV A to C, the reaction with asilicon-containing compound of formula V will not affect the group R₃ 'and accordingly, the group R₃ in the azetidine derivative of generalformula I thus obtained is identical to the group R₃ ' of thepenicillanic sulphoxide starting material.

Azetidine derivatives of formula I, wherein R₃ is a group --OR₉, whereinR₉ represents a (eventually substituted) lower alkyl group, as definedhereinabove in relation to formula I, may also be prepared by convertingan azetidine derivative of formula I, wherein R₃ represents a hydroxygroup, obtained according to one of the processes described hereinabove,into a corresponding ester.

For example, azetidine methyl esters of formula I can be prepared byreacting a corresponding azetidine derivative of formula I in the freeacid form with diazomethane in an inert organic solvent, such as diethylether. The azetidine free acid compound can be used in this reaction assuch or dissolved or suspended in an appropriate organic medium, such astetrahydrofuran.

The azetidine derivatives obtained according to one of the processesdescribed hereinabove usually have the structure indicated in formula I,i.e. with a (substituted) prop-2-enyl side chain in the molecule.Sometimes the corresponding prop-1-enyl (conventionally indicated bypropenyl)-isomers may be obtained, however. In some cases the reactionbetween a penicillanic sulphoxide derivative of formula III and asilicon-containing compound of formula V results directly in a so-callediso-azetidine (i.e. propenyl) derivative; in other cases a mixture ofpropenyl- and prop-2-enyl-isomers is obtained, from which each of theisomers can be isolated by chromatography on silica gel.

A prop-2-enyl azetidine derivative of formula I may also be convertedinto a corresponding propenyl isomer, for example by gentle heating ofthe prop-2-enyl compound (preferably in the form of an ester) withtriethylamine in a suitable organic medium, such as tetrahydrofuran.

The azetidine derivatives obtained according to the processes describedhereinabove may be separated from the reaction mixture by application ofknown procedures, for example:

a. the reaction mixture is evaporated to dryness and an organic solventis added to the residue; the azetidine derivative is then obtained byfractional precipitation and/or crystallization, or

b. the reaction mixture is evaporated to dryness and the azetidinederivative is obtained fom the residue by chromatography on silica gel.

When the reaction mixture contains an azetidine derivative in the freeacid form this may be isolated as such from the reaction mixture or itmay first be converted into a salt thereof.

In order to prepare potassium salts, for example, the reaction mixtureis first concentrated and filtered; to the filtrate is then added forexample potassium-2-ethylcaproate (if desired dissolved in a suitablesolvent, such as propanol) or potassium acetate (which is usually addedas such in the form of a powder), whereupon the precipitated potassiumsalt of the azetidine derivative is separated from the reaction mixture.

The penicillanic sulphoxides of formulae III A or B, employed asstarting materials in the process described above, can be obtained bytreatment of the corresponding penicillanic acids of the followingformula: ##EQU13## wherein R₁ is as defined hereinabove, with anoxidizing agent. For example, for this purpose the penicillanic acidderivative is treated in an inert organic solvent or water with asubstance affording active oxygen, such as sodium periodate, a per-acid,hydrogen peroxide, iodobenzene dichloride, or with ozone. Thepenicillanic sulphoxide derivatives of formulae III A or B, wherein R₃ 'is other than a hydroxy group, can be prepared from a correspondingpenicillanic free acid, either before or after its conversion into asulphoxide.

As already described above a penicillanic sulphoxide of formula III inthe free acid form can be silylated during the process of the inventionby reaction with the silicon-containing compound of formula V.

But a penicillanic sulphoxide of formula III, wherein R₃ ' represents ahydroxy group, can also be converted into a corresponding derivativewith a silylated carboxy group in a separate reaction step before theprocess of the invention is carried out, by reacting the free acid witha silylating agent, such as, for example,N,O-bis(trimethylsilyl)acetamide, in an inert organic solvent.

It will be appreciated that when silylating agents wherein two halogenatoms are attached directly to the silicon atom (such as, for example,dichloromethylsilane), are employed in this process, two molecules ofthe penicillanic acid derivative may react with one molecule of thesilylating agent, resulting in a silyl compound, wherein twopenicillanic sulphoxide acyl groups of formulae IIIC or D are attachedto the silicon atom (cf. formula IV C). Depending on the reactantsand/or reaction conditions employed it is also possible that only onemolecule of the penicillanic acid derivative reacts with one molecule ofthe dihalo-silylating agent, resulting in a silylated penicillanicsulphoxide derivative wherein one halogen atom is still attached to thesilicon atom (cf. formula IV B).

All these types of silylated penicillanic sulphoxide derivatives may beused as such in the process of the invention.

The 6β-acylamido group R₁ in the penicillanic acids of formula VI, whichare employed as starting materials in the process of preparing thepenicillanic sulphoxides of formula III, can be any group, which isknown to those skilled in the art, in the field of both natural andsynthetic penicillins and cephalosporins. The group of suitable6β-acylamido side chains R₁ include, for example, those of the followinggeneral formula: ##EQU14## wherein Q₁ represents a hydrogen atom or agroup linked to the nitrogen atom by a carbon or sulphur atom, and Q₂represents a hydrogen atom or a lower alkyl, hydroxy, amino orphenyl(lower) alkyl group, or Q₁ and Q₂ together with the nitrogen atomto which they are attached collectively represent a heterocyclic group,e.g. an optionally substituted succinimido, phthalimido, oxazolidinyl orimidazolidinyl group, or Q₁ and Q₂ together form an aralkylidene oralkylidene group, e.g. benzylidene, isopropylidene or salicylidene.

Preferably, Q₂ represents a hydrogen atom and Q₁ is a group of one ofthe following formulae: ##EQU15## wherein Z represents: a. an aliphatichydrocarbon group having at most 6 carbon atoms and which can have adouble bond.

b. a phenyl or phenoxy group, which groups may be substituted by halogenatoms, or hydroxy, lower alkyl, lower alkoxy, nitro or amino groups,

c. a(lower alkyl)thio group,

d. a 3-amino-3-carboxy-propyl group

and Y₂ represents a hydrogen atom, or a hydroxy or amino group and Y₁represents a 5-membered heterocyclic group, having 1 to 4 heteroatoms,or a phenyl group, and, when Y₂ represents a hydrogen atom, Y₁ alsorepresents a cyano or pyridylthio group.

Particularly preferred are the groups of formula VII A, wherein Zrepresents a butyl or hexyl group which groups may contain a doublebond, a phenyl or phenoxy group which groups may be substituted by ahydroxy group, or Z is a 3-amino-3-carboxy-propyl group, and groups offormula VII B, wherein Y₁ represents a 2-(3-sydnon), a 2- or 3-thienyl,a phenyl or a 1-tetrazolyl group and when Y₂ is a hydrogen atom, Y₁represents a cyano group.

Generally speaking, all penicillanic acid derivatives of formula VI,which can be obtained by fermentative procedures, are particularlysuitable starting materials for the preparation of penicillanicsulphoxide derivatives of formula III. These are, for example, thepenicillanic acid derivatives of formula VI wherein R₁ represents one ofthe following groups:

phenylacetamido, phenoxy acetamido, 2- or 3-pentenylcarbonamidoα-amino-adipoyl-δ-carbonamido, p-hydroxyphenylacetamidon-amylcarbonamido, n-heptylcarbonamido, p-Cl-, p-Br-, andp-I-phenylacetamido, (lower alkyl)mercaptoacetamido, o-F-, m-F- andp-F-phenylacetamido, 2-ethoxy-1-naphthamido and p-amino-phenylacetamido.

Moreover, R₁ preferably represents an acylamido side chain derived fromknown therapeutically active cephalosporins, for example:2-(3-sydnon)-acetamido, cyanoacetamido, 4-pyridylthioacetamido,1-tetrazolylacetamido, phthalimido, α-aminophenylacetamido,α-hydroxyphenylacetamido, 2- or 3-thienylacetamido andα-(1,4-cyclohexadienyl)-α-aminoacetamido.

It will be appreciated that before the oxidation of penicillanic acidderivatives of formula VI to the corresponding sulphoxides of formulaIII A or B, and also before these sulphoxides are reacted with asilicon-containing compound of formula V, as well as in the otherprocesses of the invention described hereinbelow, any groups in the sidechain R₁, which could be affected during these reactions, such as forexample, free amino or hydroxy groups, should be protected before thesereactions are carried out. The protection can be effected by methodswell known in the art of penicillin and cephalosporin chemistry, andpreferably introduces protective groups which can readily be removedagain.

The silicon-containing compounds according to the general formula V,some of which are known, can be prepared for example, as follows

A silylating agent including the group (R₁₀)₃ Si-(wherein R₁₀ is ashereinbefore defined) and a corresponding imide of the general formula##EQU16## wherein R₂ is as hereinbefore defined, is reacted underanhydrous conditions, preferably in an inert organic solvent (forexample one of the solvents indicated hereinabove in relation to theprocess of the invention), or an excess of the silylating agent itself.

The azetidine derivatives of general formula I are versatileintermediates in the preparation of various therapeutically activeβ-lactam compounds, as will be illustrated by the description of thefollowing processes.

The azetidine derivatives of general formula I can be used to obtaincephalosporanic acid derivatives. It has been established that alreadyduring the process of preparing the azetidine derivatives, certainamounts of corresponding Δ³ -desacetoxy cephalosporanic acid derivativesare formed in situ, which have been isolated in some instances.Preferably, the azetidine derivatives of formula I are converted intocephalosporanic acid derivatives in a separate reaction step, however.

Thus, according to another feature of the invention, there is provided anew process for the preparation of Δ³ -desacetoxycephalosporanic acidderivatives of the general formula: ##EQU17## wherein R₁ and R₃ are asdefined in relation to formula I, which comprises cyclising an azetidinederivative of general formula I (wherein the various symbols are asdefined in relation to that formula, and moreover, when R₃ represents agroup --OR₉, R₉ can also represent a silyl group of the formulae IV A toC, wherein the various symbols are as defined in relation to thoseformulae) in a dry organic solvent, in the presence of a protonfurnishing agent.

By the term "proton furnishing agent" is meant a compound which is ableto furnish the catalyzing H⁺ ions which are necessary during thecyclisation reaction. Suitable compounds which may be used for thispurpose are hydrogen bromide, hydrogen chloride, toluene-p-sulphonic andconcentrated sulphuric acid, hydrogen iodide, perchloric acid, periodicacid, nitric acid, chloric acid, iodic acid, selenic acid, substitutedacetic acids such as bromoacetic, trichloroacetic acid andtrifluoroacetic acid, substituted sulphonic acids such astrichloromethylsulphonic acid and trifluoromethylsulphonic acid,naphthalenesulphonic acid, oxalic acid, picric acid, and C--H acids,such as tris-(ethylsulphonyl)methane, pentacyanopropene,tetracyanopropene, pentacyanocyclopentadiene, tetracyanocyclopentadiene,tricyanocyclopentadiene and dinitroacetonitrile, or an acid additionsalt complex derived from these acids by combination with anitrogencontaining base, or phosphonium salts derived from these acidsby addition to ylide compounds. Suitable bases are aliphatic,cycloalipathic, aromatic or heterocyclic amines, e.g.hexamethylenetetramine, aniline, diphenylamine, N-methylaniline,dimethylaniline, pyridine and quinoline, and pyridine or quinolinesubstituted by, for example, one or more lower alkyl, aryl(lower)alkyl,aryl or mono- or di(lower)alkylamino groups, such as the picolines,2-ethylpyridine, 2-propylpyridine, 2,3-dimethylpyridine,2,5-dimethylpyridine, 2,6-dimethylpyridine, collidines and2-dimethylaminopyridine, quinoline, isoquinoline, 3-methylisoquinoline,and also pyrazole, imidazole or N-methylimidazole. Preferred bases arepyridine, substituted pyridines, quinoline, substituted quinolines,imidazole and substituted imidazoles. A preferred acid is hydrogenbromide or hydrogen chloride. In principle all bases, with the exceptionof bases containing a hydroxy group, are suitable to combine with thesaid acid, but preferably nitrogen-containing bases soluble in theorganic solvent employed and having a pKa between 4 and 10 are employed.

The cyclisation of the azetidine derivatives of general formula I intothe Δ³ -desacetoxycephalosporanic acid derivatives of formula VIII ispreferably carried out at temperatures between 40° and 120°C.

The inert organic solvent employed may be any one of those hereinbeforementioned in relation to the reaction of compounds of formulae III A orB with the silicon-containing compounds of formula V. Other suitablesolvents are for example, chlorobenzene, N,N-dimethylacetamide, dioxan,tetrahydrofuran, triethyleneglycol diethyl ether, butyl acetate, isoamylacetate, diethyl oxalate, anisole, carbon tetrachloride,dimethylsulphoxide, methyl ethyl ketone and halogenoalkanes, such as1,2-dichloroethane, 1,1-dichloroethane, 1-bromo-1-chloroethane,1,2,3-trichloropropane, methylene chloride and chloroform.

The Δ³ -desacetoxycephalosporanic acid derivatives obtained as productsof formula VIII can be separated from the reaction mixture by theapplication of known procedures. When R₃ is an amino, hydrazino or estergroup, such a group can be converted, if so desired, into a carboxygroup by methods know per se.

The Δ³ -desacetoxycephalosporanic acid derivatives of formula VIII haveantibiotic properties which make them potentially usual as medicines forhuman beings and animals, alone or in admixture with other knownmedically active ingredients. They are preferably employed fortherapeutic purposes in the form of the free acid or a non-toxic salt,such as the sodium, potassium or calcium salt.

According to another feature of the invention an azetidine derivative ofthe general formula: ##EQU18## wherein R₁ and R₂ are as hereinbeforedefined and R₃ " represents an amino, hydrazino or ester group asdefined in relation to formula I, may be converted into a2β-acetoxymethyl-2α-methyl-penam derivative of the general formula:##EQU19## wherein R₁ and R₃ " are as hereinbefore defined. The reactionmay be carried out by heating an azetidine derivative of formula I Awith thallium (III) acetate, palladium (II) acetate, mercury (II)acetate or manganese (III) acetate in an inert organic solvent, forexample, 1,1,2-trichloroethane, t-butanol or benzene, at a temperaturebetween 40° and 120°C.

During this reaction there is usually also obtained a Δ³-desacetoxycephalosporanic acid derivative of formula VIII, wherein R₁is as hereinbefore defined and R₃ has the same significance as indicatedfor R₃ " hereinabove, as well as a 3-acetoxy-cephalosporanic acidderivative of the general formula: ##EQU20## wherein R₁ and R₃ " are ashereinbefore defined.

The 2β-acetoxymethyl-penam derivatives of formula IX, some of which areknown, proved to be active against gram positive bacteria. Thesederivatives may also be converted into therapeutically valuablecephalosporins.

A 2β-acetoxymethyl-penam derivative of formula IX may first be oxidizedto a corresponding sulphoxide, which may then be converted by a ringexpansion process to a cephalosporanic derivative of the generalformula: ##EQU21## wherein R₁ and R₃ " are as hereinbefore defined.Various cephalosporin derivatives of formula XI are known to havetherapeutically interesting properties.

Accordingly, the azetidine derivatives of general formula I, prepared bythe process of this invention, may be employed:

a. in a new process of preparing Δ³ -desacetoxycephalosporanic acidderivatives of formula VIII, which have antibiotic properties,

b. to prepare therapeutically active 2β-acetoxymethyl-penam derivativesof formula IX, and

c. as intermediates in a process of preparing therapeutically valuablecephalosporin derivatives of formula XI.

It will be appreciated that the compounds of formulae VIII to XI mayalso be converted into various other useful derivatives known in thefield of penicillins and cephalosporins.

The following Examples illustrate the preparation of compounds ofgeneral formula I and the various processes of this invention. Unlessindicated otherwise, the PMR spectra were recorded on a Varian A 60instrument for solutions in deuteriochloroform containingtetramethylsilane as internal reference; the δ-values are given in ppm.

EXAMPLE 1

A. To 400 g (4 moles) of succinimide and 900 ml of triethylamine in 2700ml of toluene 780 ml of trimethylchlorosilane were added in two hourswith vigorous stirring. After refluxing and stirring for an additionalhour the mixture was allowed to cool to room temperature. Theprecipitate was filtered off, washed with 1 l of toluene and 1 l oflight petrol (40°-60 °C) and the combined filtrate and washingsconcentrated to about 700 ml. N-trimethylsilylsuccinimide was isolatedby distillation at diminished pressure. The yield was 573 g (3.35 moles)or 83.5%; boiling point 62 °C/0.3 mm Hg.

Pmr (ccl₄) δ:0.38 (s, 9); 2.62 (s, 4).

Ir (ccl₄): 1770, about 1705, 1326, 1253, about 847 cm ⁻ ¹.

B. A mixture of 5.3 g of benzylpenicillin-S-sulphoxide, 50 g ofN-acetylsuccinimide, 12.5 ml of N-trimethylsilylsuccinimide and 35 ml ofbenzene was refluxed for 16 hours. The reaction mixture (containing1-(1-trimethylsilyloxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one)was then allowed to cool to room temperature, diluted with benzene (200ml), treated with decolourizing charcoal, and evaporated to dryness. Theresidue was purified by column chromatography on silica gel using 5%acetic acid in ethyl acetate as eluent. The fractions containing themajor component of the original residue were combined, evaporated todryness and the residue triturated with diethyl ether. The precipitatewas chromatographed a second time to obtain1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothioazetidin-2-onein a pure state. The structure was confirmed by PMR and IR spectroscopy.

Pmr δ:1.85 (s, 3); 2.7 (broadened s, 4); 3.65 (s, 2); 4.71 (s, 1); about5.1 (super imposed signals, 3); about 5.3 (q, J=5 Hz, J'=8 Hz, 1); 7.25(5 ); 7.75 (d, J'=8 Hz, about 0.8 );

Ir (kbr): 3330, 3090, 3062, 3030, 1770, 1718, 1680-1650, 1525, 1495 cm⁻¹.

C. A mixture of 25 g (71 mmoles) of benzylpenicillin-S-sulphoxide, 250ml of dimethylacetamide and 75 ml (78.9 g, 460 mmoles) ofN-trimethylsilylsuccinimide was stirred for 4 hours at 105°C. Afterevaporation in vacuo the residue was dissolved in 250 ml of ethylacetate and rapidly washed twice with 125 ml of an acetic acid buffer ofpH 1.8.

The solution was dried over magnesium sulphate, treated with charcoaland after the addition of 500 ml of toluene concentrated to a smallvolume. Trituration with diethyl ether and n-hexane yielded 15 g of-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-onewith a purity of 70% as estimated by PMR, using 2,6-dichloroacetophenoneas internal standard. Thus the yield of pure azetidinone was 10.5 g(24.3 mmoles) or 34%.

D.1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one,prepared as described in Example I B, was treated with a diazomethanesolution in diethyl ether. After evaporation of the reaction mixture todryness, the residue was purified by column chromatography on silica gelusing a 5:3 (v/v) mixture of toluene and ethyl acetate, and finally onlyethyl acetate, as an eluent.

The structure of1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-oneso obtained was confirmed by mass-spectrometry and PMR and IRspectroscopy.

Pmr δ:1.87 (s, 3); 2.81 (s, 4); 3.69 (s); 3.76 (s) together 5; 4.67(slightly broadened s, 1 ); 5.08 (centre of AB_(q), δν=0.09, J_(AB) = 1Hz) about 5.15 (d, J=4.4 Hz) together 3; about 5.35 (d, J=4.4 Hz andJ'=8.8 Hz, 1 ); 7.3 and about 7.35 (d) together about 6;

Ir (kbr): 3300, 3085, 3065, 3032, 1775, 1720, 1670-1650, 1520 cm⁻ ¹.

EXAMPLE 2

A mixture of 25.5 g (70 mmoles) of the methyl ester ofbenzylpenicillin-S-sulphoxide, 410 ml of dimethylacetamide, 56 ml (340mmoles) of N-trimethylsilylsuccinimide and 1.8 ml of acetic acid wasstirred for 3.5 hours at 105 °C. After cooling to room temperature thereaction mixture was poured into a cold mixture of 500 ml ethyl acetateand 1500 ml of water. The organic layer was separated and the aqueouslayer extracted twice with 250 ml portions of ethyl acetate.

The combined extracts were washed with water, dried over magnesiumsulphate and treated with charcoal. The solution was evaporated todryness and triturated with carbontetrachloride. The residue wasfiltered off, washed with diethyl ether and dried. There was obtained1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one.

Yield: 19 g (42.7 mmoles) or 61%.

EXAMPLE 3

A mixture of 2.25 g (5 mmoles) of1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one(prepared as described in Example 2) and 1.4 ml (10 mmoles) oftriethylamine in 100 ml of tetrahydrofuran was stirred at 65 °C for 25minutes. The reaction mixture was evaporated, treated with 25 ml ofethyl acetate and evaporated once more. The residual foam was dissolvedin 50 ml of ethyl acetate, treated with charcoal and concentrated to asmall volume. The desired product crystallized upon cooling. There wasobtained1-(1-methoxycarbonyl-2-methylpropenyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one.

Yield: 1.25 g (2.9 mmoles) or 58%.

Pmr δ:2.11 (s, 3); 2.25 (s, 3); 2.71 (s, 4); 3.69 (s, 2); 3.70 (s, 3);5.00 (dd, 1; J=8 and =5 Hz); 5.25 (d, 1; J=5 Hz); 6.76 (d, 1; J=8 Hz);7.3 (s, 5).

Ir (kbr): about 3300, about 3065 and about 3030, about 1775, about 1725,1665, 1385, 1365 and 1140 cm⁻ ¹.

EXAMPLE 4

A. A mixture of 500 mg (1.5 mmoles) of benzylpenicillin-S-sulphoxide,1.5 ml of N-trimethylsilylsuccinimide, 500 mg of N-acetylsuccinimide and5 ml of dimethylformamide was stirred at 105 °C for 3.5 hours. Thereaction mixture was evaporated in vacuo and the residue triturated withacetone/toluene and the crude substance isolated by filtration.

Yield: 590 mg of a mixture, mainly consisting of succinimide and1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one.

B. A mixture of 1 g of benzylpenicillin-S-sulphoxide, 3 ml ofN-trimethylsilylsuccinimide and 10 ml of dimethylacetamide was heatedwith stirring at 105 °C for 3.5 hours. After evaporating under reducedpressure the residue of the reaction mixture was treated with 50 ml ofethyl acetate and the solution washed with tw 50 ml portions of anacetic acid/hydrochloric acid buffer of pH 1.8. The ethyl acetatesolution was dried over magnesium sulphate, treated with charcoal andafter the addition of 100 ml of toluene concentrated to about 10 ml. Thecrystals formed were isolated by filtration, washed with toluene anddiethyl ether and dried.

The yield of1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-oneso obtained was 660 mg.

C. The experiment as described in Example 4 B was repeated, but moreover1 g of N-acetylsuccinimide was added to the reaction mixture.

The yield of1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-oneso obtained was 750 mg.

D. The experiment as described in Example 4 B was repeated except that10 ml of N, N, N', N'-tetramethylurea were used as solvent instead ofdimethylacetamide.

The yield of1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-oneso obtained was 590 mg.

E. The experiment as described in Example 4 D was repeated, but moreover1 g of N-acetylsuccinimide was added to the reaction mixture. The yieldof1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-oneso obtained was 390 mg.

EXAMPLE 5

A. 250 g (1.7 moles) of phthalimide were suspended in 2.75 l ofacetonitrile; 250 ml (1.8 moles) of triethylamine were added and themixture was heated to gentle reflux; 250 ml (1.97 moles) oftrimethylchlorosilane were added in 10 minutes and the reaction mixturewas then concentrated to a thick paste. 2.5 l of light petrol (80°-110°C) were added, the triethylammonium hydrochloride was filtered off andwashed with 500 ml of light petrol. The filtrate and washings werecombined and concentrated until crystallization. After cooling in therefrigerator for several hours N-trimethylsilylphthalimide was isolatedby filtration, washed with a small portion of light petrol (40°-60 °C)and dried in vacuo.

Yield: 299 g (1.36 moles) or 80%.

Pmr:0.51 (s, 9); 7.73 (centre of super imposed signals, 4).

B. A mixture of 35 g (0.10 mole) of benzylpenicillin-S-sulphoxide, 125 g(0.57 mole) of N-trimethylsilylphthalimide, 260 ml of puredimethylacetamide and 15 ml (0.1 mole) of trimethylsilyl acetate washeated with stirring for 3.5 hours at 105 °C. The reaction mixture(containing1-(1-trimethylsilyloxycarbonyl)-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothioazetidin-2-one)was cooled to room temperature and concentrated in vacuo (40 °C, 1 mmHg). The residue was treated with 100 ml of toluene and evaporated todryness. To the residue a mixture of 250 ml of ethyl acetate, 200 ml ofwater and 50 g of crushed ice was added.

The pH was adjusted to 1.8 by addition of 4 N-hydrochloric acid andafter stirring vigorously for 15 ;l minutes at 0 °C, the mixture wasfiltered to remove phthalimide. The organic layer was separated, washedwith cold 0.02 N hydrochloric acid and treated with charcoal. Thesolution was dried with magnesium sulphate, evaporated to dryness andtriturated with ethyl acetate. The desired product precipitated and wasremoved by filtration and washed with a small volume of ethyl acetate.There was obtained1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one.

Yield: 46 g with a purity of 70% according to PMR using2,6-dichloroacetophenone as internal standard. Thus the yield of pureazetidinone was 32 g (67 mmoles) or 67%.

Pmr δ:1.89 (s, 3); 3.72 (s, 2); 4.87 (s, 1); 5.08 (broad s, 2); 5.10 (d,1; J=4.5 Hz; 5.30 (dd, 1, J=4.5 Hz and 8.5 Hz); about 7.25 (superimposed signals, 7); 7.46 (d, 1; J=8.5 Hz); 7.74 (broad s, 2).

Ir (kbr): 3300, 3085, 3060, 3030, 1770, 1740, 1712, 1665, 1600, 1530 cm⁻¹.

C. To a suspension of 14 g (29 mmoles) of1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one(prepared as described in Example 5 B) in 100 ml of tetrahydrofuran asolution of 35 mmoles of diazomethane in diethyl ether was added. Theclear solution was treated with acetic acid to remove excessdiazomethane and evaporated to dryness. After addition of 100 ml ofbenzene the solution was filtered, concentrated and chromatographed on acolumn containing 500 g of silica gel using a 4:1 (v/v) mixture oftoluene and ethyl acetate as an eluent. There was obtained1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one.

Yield: 6.2 g (12.6 mmoles) or 43%.

The structure was confirmed by mass spectrometry, PMR and IRspectroscopy.

Pmr δ:1.91 (s, 3); 3.51 (s, 3); 3.77 (s, 2); 4.77 (s, 1); 5.05 (broad s,1); 5.14 (broad s, 1); 5.13 (d, 1; J=4.5 Hz); 5.40 (dd, 1, J=4.5 Hz andJ=8.5 Hz); 7.30 and 7.83 (broad singulets, 4); 7.34 (s, 5) and 7.38 (d,1; J=8.5 Hz).

Ir (kbr): about 3310, 3090, 3067, 3038, about 1780, 1740, 1718, about1665, 1610, about 1530, 1055 cm⁻ ¹.

EXAMPLE 6

A. A mixture of 3.5 g (10 mmoles) of benzylpenicillin-S-sulphoxide, 13 g(60 mmoles) of N-trimethylsilylphthalimide, 5 g (25 mmoles) ofN-acetylphthalimide and 50 ml of dimethylformamide was stirred for 4hours at 100 °C. After evaporating the reaction mixture in vacuo. theresidue was extracted with chloroform and the resulting chloroformsolution concentrated and chromatographed on a column. The fractions,which contained the desired final product, were collected and evaporatedto dryness. After trituration with n-heptane, the residue was filteredand dried. The yield of1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-oneso obtained was 1.7 g (3.5 mmoles) or 35%. The structure was confirmedby IR and PMR spectroscopy.

B. A mixture of 2.1 g (6 mmoles) of benzylpenicillin-S-sulphoxide, 26 gof N-acetylphthalimide, 7.9 g of N-trimethylsilylphthalimide and 30 mlof toluene was stirred for 3.5 hours at 105 °C. After cooling themixture was filtered, the filtrate concentrated and chromatographed on acolumn with silica gel which was acidified with 1% of acetic acid. Thecolumn was first eluted with a 4:1 (v/v) toluene-acetone mixture toremove phthalimide and then with a 3:1 (v/v) toluene-acetone mixturecontaining 0.5% of acetic acid. The fractions containing the desiredfinal product were collected and evaporated to dryness. There wasobtained1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one.

Yield: 400 mg.

EXAMPLE 7

To a suspension of 14 g (29 mmoles) of1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothioazetidin-2-one(prepared as described in Example 5 B) in 100 ml of tetrahydrofuran, asolution of 35 mmoles of diazomethane in diethyl ether was added in 1minute. The excess diazomethane was removed by adding acetic acid to theclear solution, after which the reaction mixture was evaporated todryness. The residue was dissolved in a mixture of 100 ml oftetrahydrofuran and 7 ml of triethylamine and the solution heated at 67°C for 15 minutes. The reaction mixture was concentrated in vacuo, theresidue dissolved in ethyl acetate, treated with charcoal and againconcentrated to a small volume. The concentrate was taken up incarbontetrachloride (about 50 ml), filtered and the filtrate evaporatedto dryness. The residue was chromatographed on a column containing 500 gof silica gel, using a 3:1 (v/v) mixture of toluene and ethyl acetate asan eluent. The first product isolated from the column was7-phenylacetamido-Δdesacetoxycephalosporanic acid (66 mg). The secondproduct which could be isolated was:1-(1-methoxycarbonyl-2-methylpropenyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one.

Yield 6.4 g (13 mmoles) or 45%.

Pmr (cdcl₃, 60 Mc, δ-values in ppm, TMS as internal reference): δ:2.18(s, 3); 2.29 (s, 3); 3.59 (s, 3); 3.73 (s, 2); 4.99 (dd, 1; J=5.0 and7.5 Hz); 5.29 (d,1; J=5.0 Hz); 7.01 (d, 1; J=7.5 Hz), 7.26 (broad s, 2);7.32 (s, 5); 7.76 (broad s, 2).

Ir (kbr): about 3330, 3090, 3068, 3035, 1778, 1742, 1715, 1670, about1530, 1498, 1052 cm⁻ ¹.

A third fraction obtained from the column contained 4.4'-dithiobis[1-(1-methoxycarbonyl-2-methylpropenyl)-3-phenylacetamidoazetidin-2-one].

Yield: 365 mg (5.2 mmoles) or 18%.

Pmr δ:1.98 (s, 3); 2.23 (s, 3); 3.62 (s, 2); 3.76 (s, 3); 4.74 (dd, 1;J=4.5 Hz and 7.5 Hz); 4.97 (d, 1; J=4.5 Hz); 6.81 (d, 1; J=7.5 Hz); 7.31(s, 5).

Ir (kbr): about 3315, 3090, 3065, 3035, 1775, 1728, 1675, about 1525,1498, 1225, 1075 cm⁻ ¹.

EXAMPLE 8

A. A mixture of 30.2 g (198 mmoles) of hexahydrophthalimide, 60 ml (246mmoles) of N,O-bis(trimethylsilyl)acetamide and 240 ml of dryacetonitrile was stirred for 16 hours at room temperature and thenevaporated to dryness. The residue was crystallized from dry n-heptane;yield: 20.7 g (92 mmoles) of N-trimethylsilylhexahydrophthalimide (46%).

The structure was confirmed by PMR and IR spectroscopy.

Pmr δ:0.40 (s, 9); 1.30-1.90 (m, 8); 2.80 (t, 2; J=4 Hz).

B. A mixture of 2.3 g (6.6 mmoles) of benzylpenicillin-S-sulphoxide, 9 g(40 mmoles) of N-trimethylsilylhexahydrophthalimide and 30 ml ofdimethylformamide was heated during 2 hours at 100 °C. After evaporatingthe reaction mixture to dryness the residue (which gave virtually onespot on TLC) was purified by column chromatography on silica gel treatedwith 1% acetic acid, using 3% acetic acid in acetone as an eluent. Thefractions containing the major component of the original residue werecombined and evaporated to dryness. The residue was chromatographed asecond time on silica gel treated with 1% acetic acid, using a 8:2:1(v/v/v) mixture of toluene, acetone and acetic acid as an eluent. Therewas obtained1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-hexahydrophthalimidothio-azetidin-2-one;yield:480 mg.

Pmr δ:1.25-2.00 (m, 8); 1.91 (s, 3); 2.95 (s, 2); 3.72 (s, 2); 4.82 (s,1); 5.09 (s, 2); about 5.16 (d, 1; J=5 Hz); 5.38 (q, 4; J=3 Hz and J=7Hs); about 7.20 (d, 1); 7.50 (s, 5); 9.25 (s, 1).

Ir (chcl₃): 3380, 2940, 1775, 1720, 1665, 1340, 1160 cm⁻ ¹.

EXAMPLE 9

A. A mixture of 28.4 g (20 mmoles) of 1,5,5-trimethylhydantoin, 48 ml(14 mmoles) of N,O-bis(trimethylsilyl)-acetamide and 240 ml ofacetonitrile was stirred for 27 hours at room temperature. Afterevaporating the reaction mixture to dryness, the residue was trituratedwith n-heptane yielding 19.1 g (8.9 mmoles) of3-trimethylsilyl-1,5,5-trimethylhydantoin (31%).

Pmr δ:0.42 (s, 9); 1.34 (s, 6); 2.84 (s, 2);

Ir (chcl₃): 2950, 1755, 1690, 1595 cm⁻ ¹.

B. A mixture of 5.3 g (15 mmoles) of benzylpenicillin-S-sulphoxide, 18 g(90 mmoles) of 3-trimethylsilyl-1,5,5-trimethylhydantoin, 5.5 g (30mmoles) of 3-acetyl-1,5,5-trimethylhydantoin and 75 ml ofdimethylformamide was stirred for 3 hours at 100 °C. After evaporatingthe reaction mixture (containing1-(1-trimethylsilyloxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-(1,5,5-trimethylhydantoin-3-yl)thio-azetidin-2-onein vacuo, the residue was dissolved in chlorofrom and waschromatographed twice on a silica gel column. The fractions, whichcontained the desired final product, were collected and evaporated todryness. After trituration with n-heptane, the residue was filtered anddried. The yield was 1.3 g (2.8 mmoles) of1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-(1,5,5-trimethylhydantoin-3-yl)thio-azetidin-2-one.

The structure was confirmed by IR and PMR spectroscopy.

Pmr δ:1.36 (s, 6); 1.87 (s, 3); 2.85 (s, 3); 3.69 (s, 2); 4.86 (s, 1);4.99 (1, d; J=4.5 Hz); 5.09 (s, 2); 5.38 (1, q; J=4.5, J'=8.5 Hz); 7.29(s, 5); 7.77 (1, d; J=8.5 Hz); 8.28 (s, 1).

C. A mixture of 350 mg (1 mmole) of benzylpenicillin-S-sulphoxide, 3.9 g(23 mmoles) of 3-acetyl-1,5,5-trimethylhydantoin, 1.2 g (6 mmoles) of3-trimethylsilyl-1,5,5-trimethylhydantoin and 5 ml of toluene wasstirred for 2 hours at 100°C. After evaporating the reaction mixture todryness, the residue was purified in the same way as described inExample 8. There were obtained 240 mg of1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-(1,5,5-trimethylhydantoin-3-yl)thio-azetidin-2-one; yield 51%.

EXAMPLE 10

A. A mixture of 14.1 g (0.1 mole) of 3,3-dimethylglutarimide, 26 ml (0.1mole) of N,O-bis(trimethylsilyl)acetamide and 120 ml of acetonitrile wasstirred for 16 hours at room temperature. After evaporating the solutionin vacuo to dryness, the residue was dissolved in 200 ml of n-heptaneand this solution was set aside for 16 hours at 0°C. After thecrystalline precipitate was filtered off, the filtrate was concentratedto 50 ml and set aside again for 16 hours at 0°C. A second crop ofcrystals was collected. In this way a total amount of 15.6 g (0.073mole) of N-trimethylsilyl-3,3-dimethylglutarimide was obtained; yield:73%.

The structure was confirmed by PMR and IR spectroscopy.

Pmr δ:0.38 (s, 9); 1.07 (s, 6); 2.40 (s, 4).

B. A mixture of 2.3 g(6.5 mmoles) of benzylpenicillin-S-sulphoxide, 8.5g (40 mmoles) of N-trimethylsilyl-3,3-dimethylglutarimide and 30 ml ofdimethylformamide was stirred during 3.5 hours at 100°C. Afterconcentrating the reaction mixture (containing1-(1-trimethylsilyl/carbonyl-2-methylpropenyl)-3-phenylacetamido-4-(3,3-dimethylglutarimido)thio-azetidin-2-oneto dryness the residue was dissolved in a mixture of 50 ml of aceticacid and 50 ml of water containing 2% acetic acid.

After adjusting the pH to 1.8 with N 4 hydrochloric acid the layers wereseparated and the organic layer was treated with decolourizing carbonand concentrated. After evaporating the solvent in vacuo, the residuewas dissolved in a small amount of chloroform and chromatographed on asilica gel column treated with 1% acetic acid.

A 5:2:1 (v/v/v) mixture of toluene, acetone and acetic acid was used asan eluent. The major fraction was evaporated to dryness and the residuewas washed with some methyl isobutyl ketone. There were obtained 430 mgof1-(1-carboxy-2-methylpropenyl)-3-phenylacetamido-4-(3,3-dimethylglutarimido)thioazetidin-2-one.

Pmr (cdcl₃ + DMSO-d6 + CD₃ COCD₃)

δ:1.02 (s, 6); 2.14 (s, 3); 2.27 (s, 3); 2.57 (s, 4); 3.67 (s, 2); 5.05and 5.15 (dd, 1; J=5 Hz and J=7.5 Hz); 5.37 (d, 1; J=5 Hz); 7.33 (s, 5);7.94 (d, 1; J=7.5 Hz); 8.93 (s, 1).

Ir (kbr): 3320, 2960, 1775, 1700, 1500, 1220, 1120 cm⁻ ¹.

EXAMPLE 11

A. A mixture of 15.5 g (0.1 mole) of 3-ethyl-3-methylglutarimide, 25 ml(0.1 mole) of N,O-bis(trimethylsilyl)acetamide and 120 ml ofacetonitrile was stirred for 16 hours at room temperature andconcentrated. After dissolving the residue in 50 ml of heptane thissolution was set aside at 0°C for 24 hours. The crystalline material wasthen filtered off, as well as a second crop obtained from the motherliquor.

Yield:3.5 g of N-trimethylsilyl-3-ethyl-3-methylglutarimide.

Pmr δ:0.39 (s, 9); about 1.00 (m, 8); 2.39 (s, 4).

B. After adding 9.1 g (40 mmoles) ofN-trimethylsilyl-3-ethyl-3-methylglutarimide to a solution of 2.3 g (6.5mmoles) of benzylpenicillin-S-sulphoxide in 30 ml of dimethylformamidethe reaction mixture was stirred during 3.5 hours at 100°C and thenconcentrated in vacuo. After dissolving the residue (containing1-(1-trimethylsilyloxycarbonyl-2-methylpropenyl)-3-phenylacetamido-4-(3-ethyl-3-methylglutarimido)thio-azetidin-2-one)in a mixture of 50 ml of acetic acid and 50 ml of water containing 2%acetic acid, the pH was adjusted to 1.8 with 4 N hydrochloric acid andthe layers were separated. The ethyl acetate layer was treated withdecolourizing carbon and concentrated in vacuo; the residue wasdissolved in a small amount of chloroform and chromatographed on asilica gel column impregnated with 1% acetic acid, using a 8:2:1 (v/v/v)mixture of toluene acetone and acetic acid as an eluent. The majorfraction was evaporated to dryness; there were obtained 120 mg of1-(1-carboxy-2-methylpropenyl)-3-phenylacetamido-4-(3-ethyl-3-methylglutarimido)thio-azetidin-2-one.

Pmr (cdcl₃ and a trace of DMSO-d6)

δ:0.86, 0.95 and 0.96 (main signals, 8); 2.15 (s, 4); 2.29 (s, 3); 2.29(s, 3); 2.55 (s, 4); 3.68 (s, 2); 5.07 and 5.16 (dd, 1; J=5 Hz and J=7.5Hz); 5.37 (d, 1; J=5 Hz); 7.33 (s, 5); 7.54 (s, 5); about 9.00 (s, broad1).

Ir (kbr): 3350, 2975, 1780, 1700, 1550, 1220 cm⁻ ¹.

EXAMPLE 12

A. To a solution of 20 g (57 mmoles) ofphenoxymethylpenicillin-S-sulphoxide in 200 ml of dimethylacetamide wasadded 60 ml (350 mmoles) of trimethylsilylsuccinimide After stirring thereaction mixture for 3 hours at 100°C, the solvent was removed underreduced pressure and the residue (containing1-(1-trimethylsilyloxycarbonyl-2-methylprop-2-enyl)3-phenoxyacetamido-4-succinimidothio-azetidin-2-one)was dissolved in a mixture of 200 ml of ethyl acetate and 200 ml ofwater containing 2% of acetic acid. After adjusting the pH to 1.7 theethyl acetate layer was treated with decolourizing carbon, diluted with500 ml of toluene and concentrated. The thus obtained amorphous solidwas filtered off, washed with diethyl ether, dissolved in a minimumvolume of chloroform and chromatographed on a silica gel columnimpregnated with 1% acetic acid, using a 6:2:1 (v/v/v) mixture oftoluene, acetone and acetic acid as an eluent. The fractions containingthe desired product were combined and evaporated in vacuo. There wereobtained 2.6 g of 1-(1-carboxy-2-methylprop-2-enyl)-3-phenoxyacetamido-4-succinimidothio-azetidin-2-one.

Pmr δ:1.91 (s, 3); 2.79 (s, 4); 4.64 (s, 2); 4.83 (s, 1); 5.16 (s, 2);5.17 (d, 1; J=4.5 Hz); 5.45 and 5.58 (dd, 1; J=4.5 Hz and J=8 Hz);6.80-7.40 (m, 5); 8.61 (d, 1; J=8 Hz).

Ir (kbr): 3300, 2950, 1775, 1725, 1250, 1150 cm⁻ ¹.

B. A mixture of 550 mg (1.5 mmole) ofphenoxymethylpenicillin-R-sulphoxide, 1.5 ml (8.8 mmoles) ofN-trimethylsilylsuccinimide and 5 ml of dimethylacetamide was stirredfor 2 hours at 80°C and then concentrated.

The oil thus obtained was chromatographed on a silica gel columnimpregnated with 1% acetic acid, using a 6:2:1 (v/v/v) mixture oftoluene, acetone and acetic acid as an eluent. The fractions containingthe desired product were combined and evaporated in vacuo. There wereobtained 120 mg of white1-(1-carboxy-2-methylprop-2-enyl)-3-phenoxyacetamido-4-succinimidothio-azetidin-2-one.

The structure was confirmed by PMR and IR spectroscopy.

EXAMPLE 13

A mixture of 12.9 g (30 mmoles) ofβ-ethoxy-α-naphthyl-penicillin-S-sulphoxide, 30 ml (175 mmoles) ofN-trimethylsilylsuccinimide and 100 ml of dimethylacetamide was stirredduring 4.5 hours at 100°C. After removing the solvent under reducedpressure and adding 100 ml of toluene to the oily residue, succinimidecrystallized. After filtration, the filtrate (containing1-(1-trimethylsilyloxycarbonyl-2-methylprop-2-enyl)-3-β-ethoxy-.alpha.-naphthoylamino-4-succinimidothio-azetidin2-one)was evaporated in vacuo. The residue was dissolved in 150 ml of ethylacetate and this solution was cooled to 4°C and washed three times with500 ml of an aqueous acetic acid solution buffered with 4 N hydrochloricacid to pH 2.6.

After drying and treating the ethyl acetate solution with decolourizingcarbon, the solvent was removed in vacuo and the residue was purified bychromatography on a silica gel column, using a 1:2:8 (v/v/v) mixture ofacetic acid, acetone and toluene as an eluent. There was obtained 1.0 gof1-(1-carboxy-2-methylprop-2-enyl)-3-β-ethoxy-α-naphthoylamino-4-succinimidothio-azetidin-2-one.

Pmr δ:1.31 (t, 3; J=6.5 Hz); 1.80 (s, 1); 2.57 (s, 4); 4.05 (q, 2; J=6.5Hz); 4.84 (s, 1) 5.00 (s, 2); 5.10 (d, 1; J=4.5 Hz); 5.41 and 5.53 (dd,1; J=4.5 Hz and J=7.5 Hz); about 6.85-7.80 (m, 6); 8.06 (d, 1: J=7.5Hz).

Ir (kbr): 3300, 3000, 1790, 1780, 1735, 1520, 1310, 1260, 1160 cm⁻ ¹.

EXAMPLE 14

A mixture of 1.8 g (5 mmoles) of phenoxymethylpenicillin-S-sulphoxideand 6.6 g (30 mmoles) of N-trimethylsilylphthalimide in 35 ml ofdimethylacetamide was heated at 100°C for 2 hours. The reaction mixture(containing1-(1-trimethylsilyloxycarbonyl-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothioazetidin-2-one)was evaporated to dryness, treated with 30 ml of dichloromethane andfiltered. The filtrate was concentrated and purified by chromatographyon a silica gel column impregnated with 1% acetic acid, using a 4:1(v/v) mixture of toluene and acetone with 0.5% acetic acid as an eluent.There was obtained1-(1-carboxy-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one.

Yield: 1.11 g (2.24 mmoles) or 45%.

Pmr δ:1.97 (s, 3); 4.66 (s, 2); 4.85 (s, 1); 5.12 (broad s, 2); 5.24 (d,1; J=5.0 Hz); 5.50 (dd, 1; J=5.0 Hz and J=8.5 Hz); 6.9-7.9 (superimposed signals, 9); 8.39 (d,1; J=8.5 Hz).

Ir (kbr): 3300, 1780, 1740, 1710, 1660, 1590, 1520, 1490, 1360, 1290,1220, 1170, 1090, 1060 cm⁻ ¹.

EXAMPLE 15

A. A mixture of 200 g (0.57 moles) of benzylpenicillin-S-sulphoxide, 600ml (3.68 moles) of N-trimethylsilylsuccinimide and 2000 ml ofdimethylacetamide was stirred under nitrogen for 5 hours at 100°C. Afterconcentrating, the reaction mixture was diluted with 2000 ml of ethylacetate and washed three times with a total amount of 1750 ml of a coldbuffered solution of 2% acetic acid, adjusted with 2 N hydrochloric acidto pH 1.8.

Then the organic layer was filtered, the filtrate was dried on magnesiumsulphate, treated with decolourizing charcoal, concentrated to a thickoil and dissolved in some chloroform. The mixture was chromatographed ona silica gel column using a 1:4 (v/v) mixture of chloroform and toluene,a 5:1 (v/v) mixture of toluene and acetone and a 5:1 (v/v) mixture oftoluene and acetone with 1% acetic acid, respectively, as eluents. Afterrepeating this procedure for the right fractions, two products could beisolated, viz.1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one(19 g) and 7-phenylacetamido-Δ³ -desacetoxycephalosporanic acid (10 g).The structures were confirmed by PMR and IR spectroscopy.

B.A solution of 1.1 g (3 mmoles) of 6-phthalimidopenicillanicacid-R-sulphoxide in 20 ml of dimethylacetamide was treated with 4 g (18mmoles) of N-trimethylsilylphthalimide at 100°C. After 4 hours themixture (containing1-(1-trimethylsilyloxycarbonyl-2-methylprop-2-enyl)-3-phthalimido-4-phthalimidothio-azetidin-2-one)was concentrated, the residue was dissolved in 30 ml of dichloromethaneand the solution was filtered. The filtrate was purified bychromatography on a silica gel column impregnated with 1% acetic acid,using a 4:1 (v/v) mixture of toluene and acetone containing 0.5% aceticacid as an eluent. There were obtained 100 mg of 7-phthalimido-Δ³-desacetoxycephalosporanic acid and 210 mg of1-(1-carboxy-2-methylprop-2-enyl)-3-phthalimido-4-phthalimidothio-azetidin-2-onecontaminated with dimethylacetamide.

Pmr δ2.14 (s, 3); 5.13 (s, 1); 5.32 (s, 2); 5.44 (d, 1, J=5.0 Hz); 5.75(d, 1, J=5.50 Hz); 7.7-8.1 (super imposed signals, 8).

IR (KBr): 1780, 1770, 1740, 1710, 1600, 1390, 1280, 1050 cm⁻ ¹.

EXAMPLE 16

A mixture of 430 mg of1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one(prepared as described in Example 1 B),0.8 ml of N,O-bis(trimethylsilyl)acetamide, 0.2 ml of a 5.8 molar solution of α-picoline hydrobromide indichloroethane, 0.2 ml of α-picoline and 7 ml of benzene was heated for3 hours at 80°C. The reaction mixture was then poured into ice-water andethyl acetate. After washing with ethyl acetate at pH 7, the aqueouslayer was extracted with ethyl acetate at pH 3.2. The organic solutionwas then evaporated to dryness and the residue triturated with diethylether. The obtained product was identical to an authentic sample of7-phenylacetamido-Δ³ -desacetoxy-cephalosporanic acid according tothin-layer chromatography,

Ir spectroscopy and a microbiological assay using Escherichia coli asthe test microorganism; yield: 100 mg or 30%.

EXAMPLE 17

A mixture of 45 mg of1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one(preparedas described in Example 1 D),0.05 ml of N,O-bis(trimethylsilyl)acetamide, 0.02 ml of a 5.8 molar solution of α-picolinehydrobromide in dichloroethane, 0.02 ml of α-picoline and 0.7 ml ofbenzene was heated for 3 hours at 80°C. The reaction mixture was thendiluted with 3 ml of ethyl acetate, washed with a hydrochloric acidsolution and water, dried on molecular sieves and evaporated to dryness.The residue was then dissolved in chloroform and treated withtetrachloromethane and ligroin. The precipitate was filtered off, washedwith ligroin and dried. It was identical to an authentic sample of themethyl ester of 7-phenylacetamido-Δ³ -desacetoxycephalosporanic acidaccording to thin-layer chromatography; yield: 10 mg or 29%.

The structure was confirmed by IR and PMR spectroscopy.

Pmr (cdcl₃ and DMSO-d6, 60 Mc) δ:2.09 (s, 3); 3.10 (d, 1; J=18 Hz); 3.47(d, 1; J=18 Hz); 3.58 (s, 2); 3.78 (s, 3); 4.87 (d, 1; J=4.5 Hz); 5.56and 5.71 (dd, 1; J=4.5 Hz and J=8 Hz): 7.2 (s, 5); 8.01 (d, 1; J=8 Hz).

Ir (kbr): 3275, 1770, 1720, 1640, 1530 cm⁻ ¹.

EXAMPLE 18

A mixture of 3.8 g (8.5 mmoles) of1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one(prepared as described in Example 1 D), 3.4 g (8.3 mmoles) of thallium(III) acetate. 1.5 H₂ O and 175 ml of 1,1,2-trichloroethane was stirredunder nitrogen for 4 hours at 80°C. The solvent was removed in vacuo,the residue was extracted with methylene chloride and ethyl acetate.After concentrating the extract, the residue was dissolved in a smallamount of chloroform and separated by chromatography on a silica gelcolumn, using a 1:1 (v/v) mixture of toluene and ethyl actate as aneluent. There were obtained two fractions, described in order ofelution.

The first fraction was evaporated to dryness, the residue was dissolvedin a small volume of methylene chloride. Upon precipitation with diethylether there were obtained 120 mg of the methyl ester of7-phenylacetamido-Δ³ -desacetoxycephalosporanic acid.

From the mother liquor of this fraction could be obtained 360 mg ofanother compound: methyl2β-acetoxymethyl-2α-methyl-6β-phenylacetamidopenam-3.alpha.-carboxylatein the form of an oily residue.

Pmr δ:1.45 (s, 3); 2.02 (s, 3); 3.63 (s, 2); 3.77 (s, 3); 3.64 and 4.31(ABq, 2; J=12 Hz); 4.64 (s, 1); 5.53 (d, 1; J=4 Hz); 5.65 (dd, 1; J=4 Hzand J=9 Hz); 6.81 (d, 1; J=9 Hz); 7.29 (s, 5).

Ir (chcl₃): 3370, 1780, 1750, 1680, 1500 cm⁻ ¹. The second fraction wasconcentrated in vacuo and chromatographed a second time. There wereobtained 360 mg of methyl3-acetoxy-3-methyl-7-phenylacetamidocepham-4-carboxylate.

Pmr δ1.52 (s, 3); 1.80 (s, 3); 3.24 and 3.69 (ABq, 2; J=14 Hz); 3.64 (s,2); 3.75 (s, 3); 4.70 (s, 1); 5.24 (d, 1; J=4.5 Hz); 5.47 and 5.61 (dd,1; J=4.5 Hz and J=9 Hz); 6.28 (d, 1; J=9 Hz); 7.29 (s, 5).

Ir (chcl₃): 3430, 1770, 1750, 1680, 1500 cm⁻ ¹.

EXAMPLE 19

A mixture of 4.4 g (10 mmoles) of the benzyl ester ofbenzylpenicillin-S-sulphoxide, 12.5 g (57 mmoles) ofN-trimethylsilylphthalimide, 0.2 ml (4 mmoles) of acetic acid and 26 mlof dimethylacetamide was stirred for 3 hours at 105°C. Thedimethylacetamide was evaporated, while toluene was added, whereafterphthalimide was filtered off. To the filtrate were added 50 ml of ethylacetate and water, adjusted with hydrochloric acid to pH 2. Afterstirring for 5 minutes a second crop of phthalimide was filtered off,the two layers were separated and the organic layer was washed withwater, treated with decolourizing carbon, dried with magnesium sulphateand concentrated to dryness. The residue was extracted with a smallamount of toluene (10-25 ml) and this extract was chromatographed on asilica gel column, using toluene-ethylacetate mixtures (from 5:1 to 3:2;v/v) as eluents. There were obtained 300 mg of1-(1-benzyloxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one.

Pmr δ:1.92 (s, 3); 3.73 (s, 2); 4.89 (s, 1); 5.08 (s, 3); 5.12 (s, 1);5.18(d,1; J=4.5 Hz); 5.36 (dd, 1; J=4.5 Hz and J=8 Hz); 7.26 (d, 1; J=8Hz); about 7.20-7.60 (m, 10); 7.77 (s, 4).

Ir (kbr): 3300, 1775, 1735, 1705, 1660, 1280, 1050 cm⁻ ¹.

Another crop of 3.4 g of the same product was obtained which was stillcontaminated with some starting material.

EXAMPLE 20

A mixture of 4.8 g (10 mmoles) of the p-nitrobenzyl ester ofbenzylpenicillin-S-sulphoxide, 12.5 g (57 mmoles) ofN-trimethylsilylphthalimide, 0.1 ml (2 mmoles) of acetic acid and 26 mlof dimethylacetamide was stirred for 4 hours at 105°C. The solvent wasremoved under reduced pressure and to the oily residue were added 50 mlof ethyl acetate and 100 ml of water; the mixture was acidified withhydrochloric acid to pH 2. The mixture, which contained a precipitate,was treated with decolourizing carbon and filtered. The organic layerwas washed with water, dried and evaporated.

The residue was extracted with a small amount of toluene (25 ml) andthis extract was chromatographed through silica gel using a 4:1 (v/v)mixture of toluene and ethyl acetate as an eluent. This afforded a foam,which was treated with decolourizing carbon in ethyl acetate. Afterfiltration and evaporation to dryness, there were obtained 140 mg of1-(1-p-nitrobenzyloxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one.

Pmr δ:1.91 (s, 3); 3.76 (s, 2); 4.97 (s, 1); 5.07 (d, 1; J=4.5 Hz); 5.07(s, 1); 5.15 (s, 1); 5.18 (s, 1); 5.32 (dd, 1; J=4.5 Hz and J=8 Hz);7.27 (d, 1; J=8 Hz); 7.36 (s, 5); 7.44 (d, 2; J=8.5 Hz); 7.78 (s, 4);8.11 (d, 2; J=8.5 Hz).

Ir (kbr): 3400, 1780, 1740, 1710, 1510, 1350, 1290, 1060 cm⁻ ¹.

The second component eluted was the isomer1-(1-p-nitrobenzyloxycarbonyl-2-methylpropenyl)-3-phenylacetamido-4-phthalimidothioazetidin-2-one(511 mg), isolated as a crystalline material from ethyl acetate.

Pmr δ:2.25 (s, 3); 2.35 (s, 3); 3.75 (s, 2); 4.91 (dd, 1; J=5.5 Hz andJ=7.5 Hz); 507 and 5.32 (q, 2; J=14 Hz); 518 (d, 1; J=5.5 Hz); 6.67 (d,1; J=7.5 Hz); 7.38 (s, 5); 7.42 (d, 2; J=8.5 Hz); 7.83 (s, 4); 8.07 (d,2; J=8.5 Hz);

Ir (kbr): 3350, 1785, 1740, 1720, 1520, 1355, 1300, 1230, 1070, 1080 cm⁻¹.

EXAMPLE 21

A mixture of 5 g (10 mmoles) of the trimethylsilylester ofbenzylpenicillin-S-sulphoxide, 12.5 g (57 mmoles) ofN-trimethylsilylphthalimide, 0.6 ml (10 mmoles) of acetic acid and 26 mlof dimethylacetamide was stirred for 3.5 hours at 105°C. The reactionmixture was cooled to room temperature and concentrated in vacuo.

To the residue was added 100 ml of cold ethyl acetate and 50 ml of coldwater, acidified with hydrochloric acid (pH 1.5). The mixture wasfiltered and the organic layer was washed with water, treated withdecolourizing carbon, dried and evaporated. The residue was extractedwith a small amount of toluene. This extract was treated withdecolourizing carbon and the solvent was removed in vacuo.

There were obtained 3.8 g of1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one;yield 79%. The structure was confirmed by PMR and IR spectroscopy.

EXAMPLE 22

A mixture of 2.8 g (7 mmoles) of the t-butylamide ofbenzylpenicillin-S-sulphoxide, 8.8 g (40 mmoles) ofN-trimethylsilylphthalimide, 0.2 ml (4 mmoles) of acetic acid and 18 mlof dimethylacetamide was stirred for 3.5 hours at 105°C. After coolingthe reaction mixture was poured out into 150 ml of water and 50 ml ofethyl acetate. The layers were separated and the water layer wasextracted three times with ethyl acetate. The combined organic layerswere dried and concentrated. After filtration of the precipitatedphthalimide, n-hexane was added to the filtrate. There were obtained 3.5g of a solid material, which gave virtually one spot on the thin-layerchromatogram. After chromatography through silica gel, using mixtures oftoluene and ethyl acetate (from 4:1 to 2:1; v/v) as eluents, there wereobtained: 900 mg of1-(1-t-butylamidocarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one;yield 24%.

Pmr (dmso-d6; 60 Mc) δ:1.26 (s, 9); 1.80 (s, 3); 3.69 (s, 2); 4.90(broad s, 3); 4.97 (dd, 1; J=5 Hz and J=7 Hz); 5.35 (d, 1; J=5 Hz); 7.36(s, 5); 7.96 (s, 4); 9.37 (d, 1; J=7 Hz).

Ir (kbr): 3350, 2970, 1780, 1730, 1710, 1650, 1530, 1290, 1060 cm⁻ ¹.

EXAMPLE 23

A mixture of 7 g (20 mmoles) of benzylpenicillin-S-sulphoxide, 21 ml(336 mmoles) of N-trimethylsilylsuccinimide and 70 ml ofdimethylacetamide was stirred for 3,5 hours at 105°C. After removing thesolvent in vacuo, adding some toluene and removing the toluene in vacuo,the residue was stirred in a mixture of ethyl acetate and water (pH =1.5) at 0°C. The organic layer was then treated with decolourizingcharcoal dried and concentrated. After filtering off the precipitate,the filtrate was diluted with ethyl acetate to a volume of 200 ml. Tothis solution was added 16 ml of a 0.46 molar solution ofpotassium-2-ethyl caproate in n-propanol and a few drops of diethylether. The precipitate, the potassium salt of1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one,was filtered off, washed with diethyl ether and dried; yield: 2.24 g.

Pmr (dmso-d₆): δ: 1.85 (s, 3); 2.72 (s, 4); 3.62 (s, 2); 4.56 (s, 1);4.95 (s, broad, 1); 5.14 (dd, 1; J=5 Hz and J=8 Hz); 5.50 (d, 1; J=5Hz); 7.35 (s, 5); 9.18 (d, 1; J=8 Hz)

Ir (kbr): 3350, 1760, 1720, 1660, 1610, 1315, 1160 cm⁻ ¹

We claim:
 1. Azetidine derivatives of the formula ##EQU22## wherein R₁represents a penicillin- or cephalosporin acylamido group, R₂represents: ##EQU23## and when said group represents a phenylene - thisgroup may carry one to four further substitutents selected from thegroup consisting of halogen and lower alkyl, lower alkenyl and phenylR₃represents an amino group of the formula ##EQU24## wherein R₇ representsa hydrogen atom or a lower alkyl and R₈ represents a lower alkyl, or R₃represents a N,N'-disubstituted hydrazino group wherein the substituentsare lower alkyl, or R₃ represents --OR₉, wherein R₉ represents ahydrogen atom, a lower alkyl optionally substituted by 1 to 3 halogenatoms or by 1 or 2 phenyl groups, wherein the phenyl groups may besubstituted by a methoxy or a nitro, or R₉ represents a phenacyl groupor an alkali metal or alkaline earth metal ion and correspondingazetidine derivatives wherein the double bond in the propenyl side chainhas been shifted from the 2- to the 1-position.
 2. Azetidine derivativesaccording to claim 1, wherein the group ##EQU25## represents aphthalimido and hexahydrophthalimido group.
 3. Azetidine derivativesaccording to claim 1, wherein R₉ is selected from the group consistingof alkali metal and alkaline earth metal ions.
 4. Azetidine derivativesaccording to claim 1, wherein R₉ represents a hydrogen atom, a methyl orbenzyl group or a sodium or potassium ion.
 5. Azetidine derivativesaccording to claim 1, wherein R₉ represents a hydrogen atom or methylgroup.
 6. Azetidine derivatives according to claim 1, wherein the group##EQU26## represents a phthalimido group and R₉ represents a hydrogenatom or a methyl group.
 7. Azetidine derivatives according to claim 1,wherein R₁ represents a group of the general formula: ##EQU27## whereinQ₁ represents a hydrogen atom or a group linked to the nitrogen atom bya carbon or sulphur atom, and Q₂ represents a hydrogen atom or a loweralkyl, hydroxy, amino or phenyl(lower) alkyl group, or Q₁ and Q₂together with the nitrogen atom to which they are attached collectivelyrepresent a heterocyclic group, or Q₁ and Q₂ together form anaralkylidene or alkylidene group.
 8. Azetidine derivatives according toclaim 1, wherein R₁ represents a group of the general formula: ##EQU28##wherein Q₂ represents a hydrogen atom and Q₁ is a group of the followingformula: ##EQU29## and Y₂ represents a hydrogen atom, or a hydroxy oramino group and Y₁ represents a 5-membered heterocyclic group, having 1to 4 heteroatoms, or a phenyl group, and, when Y₂ represents a hydrogenatom, Y₁ also represents a cyano or pyridylthio group.
 9. Azetidinederivatives according to claim 1, wherein R₁ represents a group of thegeneral formula: ##EQU30## wherein Q₂ represents a hydrogen atom and Q₁is a group of the following formula:

    Z CH.sub.2 CO --                                           VII A

wherein Z represents: a. an aliphatic hydrocarbon group having at most 6carbon atoms and which can have a double bond, b. a phenyl or phenoxygroup, which groups may be substituted by halogen atoms, or hydroxy,lower alkyl, lower alkoxy, nitro or amino groups, c. a(lower alkyl)thiogroup, or d. a 3-amino-3-carboxy-propyl group.
 10. Azetidine derivativesaccording to claim 8, wherein Y₁ represents a 2-(3-sydnon), a 2- or3-thienyl, a phenyl or a 1-tetrazolyl group, and when Y₂ is a hydrogenatom, Y₁ represents a cyano group.
 11. Azetidine derivatives accordingto claim 9, wherein Z represents a 3-amino-3-carboxy-propyl group, abutyl or hexyl group which groups may contain one double bond, or aphenyl or phenoxy group which groups may be substituted by a hydroxygroup.
 12. Azetidine derivatives according to claim 1, wherein R₁ isselected from the group consisting of the followinggroups:phenylacetamido, phenoxy acetamido, 2-or 3-pentenylcarbonamidoα-amino-adipoyl-δ-carbonamide, p-hydroxyphenylacetamidon-amylcarbonamido, -n-heptylcarbonamido, p-Cl-, p-Br-, andp-I-phenylacetamido, (lower alkyl)mercaptoacetamido, o-F-, m-F-andp-F-phenylacetamido, 2-ethoxy-1-naphthamido, p-aminophenylacetamido,2-(3-sydnon)-acetamido, cyanoacetamido, 4-pyridylthioacetamido,1-tetrazolylacetamido, phthalimido, α-aminophenylacetamido,α-hydroxyphenylacetamido, 2- or 3-thienylacetamido andα-(1,4-cyclohexadienyl)-α-aminoacetamido.
 13. Azetidine derivativesaccording to claim 1, wherein R₁ represents a phenylacetamido group, thegroup: ##EQU31## represents a phthalimido group and R₉ represents ahydrogen atom or a methyl group.
 14. Azetidine derivative according toclaim 1, which is1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one.15. Azetidine derivative according to claim 1, which is1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothioazetidin-2-one.16. Azetidine derivative according to claim 1, which is1-(1-methoxycarbonyl-2-methylpropenyl)-3-phenylacetamido-azetidin-2-one.17. Azetidine derivative according to claim 1, which is1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-hexahydrophthalimidothioazetidin-2-one.18. Azetidine derivative according to claim 1, which is1-(1-carboxy-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one.19. Azetidine derivative according to claim 1, which is1-(1-carboxy-2-methylprop-2-enyl)-3-phthalimido-4-phthalimidothio-azetidin-2-one.20. Azetidine derivative according to claim 1, which is1-(1-benzyloxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothioazetidin-2-one.21. Azetidine derivative according to claim 1, which is1-(1-p-nitrobenzyloxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one.22. Azetidine derivative according to claim 1, which is1-(1-p-nitrobenzyloxycarbonyl-2-methylpropenyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one.23. Azetidine derivative according to claim 1, which is1-(1-t-butylamidocarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one.